Dr. Bailey-Wilson is collaborating with Drs. Barbara and Ronald Klein and Sudha Iyengar on analyses of existing family data from the Beaver Dam Eye Study (BDES). A private census of the town and township of Beaver Dam, Wisconsin was performed and all individuals between the ages of 43-84 were asked to enroll, given extensive eye examinations and asked to fill out a questionnaire that measures environmental risk factor exposures. We have previously analyzed STRP genome-wide scan (GWS) data on the entire Beaver Dam cohort of families for glaucoma, IOP, refractive error, myopia, hyperopia, and various forms of cataracts. Linkage analyses using a new SNP linkage panel with multiple traits including: refraction, myopia was previously performed. Analyses of dense SNPs for finemapping of Chromosome 19 for IOP and 2 smaller glaucoma-associated regions on chromosomes 5 and 6 are currently underway. Genotyping of the whole exome SNP array is being performed in the families and unrelated individuals in this cohort and both linkage and association analyses will be performed for various eye disease traits. In addition this study has joined the Consortium for Refractive Error and Myopia (CREAM), a consortium of over 50 international studies who will work together to perform meta-analyses of refractive error traits. A study of the genetics of myopia with Dr. Dwight Stambolian is ongoing. Dr. Stambolian has collected pedigrees with myopia from 4 populations. Analyses of refractive error in the Ashkenazi Jewish and Amish families have revealed evidence of a QTL on chromosome 1. A set of about 1500 SNPs were genotyped in our Ashkenazi and Amish families to follow up the linkage of refractive error on chromosome 1; these analyses confirmed our previous linkage of refractive error to a locus on 1p34-p36. During follow-up of our previous chromosome 22 linkage results for myopia, we have used association and sequencing methods to narrow the region to 3 candidate loci. We are carefully examining these candidates to determine which is the susceptibility gene. We have analyzed additional deep sequencing data of this region in the past year and are currently performing confirmatory studies of a candidate mutation. Drs. Stambolian, Bailey-Wilson, Wojciechowski and Thomas Meitinger (Germany) are collaborating to perform a genome-wide association study (GWAS) of refractive error in the AREDS and KORA population cohorts and are performing meta-analyses of results from these data with results from the Framingham Eye Study (FES), the MESA study and the OGP-Talana study in Sardinia. We have confirmed discoveries from these data in several other GWAS and are preparing manuscripts for publication. We have also contributed results from our AREDS, KORA and FES GWAS to a confirmation meta-analysis of refractive error candidate associated regions on 15q and were coauthors on a paper presenting these results this year. Whole exome SNP array genotyping is ongoing in all of the Family Myopia Study families, the AREDS cohort and an additional 4000 unrelated individuals. We will analyze these data using multiple approaches to detect rare variants that contribute to refractive error traits. Dr. Bailey-Wilson is also one of the leaders of CREAM, an international consortium on meta-analysis of refractive error related traits and is co-Chair of CREAM Analysis Working Group 2. The collaborative analyses planned by CREAM will increase power to detect common alleles with small effects on refractive error as a quantitative trait and its related clinical disorders, myopia, hyperopia and astigmatism. Dr. Bailey-Wilson is collaborating with Dr. Hasan Albacha-Hejazi of the Syrian Arab Republic on a study of oral clefts. Data collection is ongoing in the Syrian Arab Republic. We are collaborating with Dr. Terri Beaty of Johns Hopkins Bloomberg School of Public Health on DNA sequencing studies. We are currently analyzing whole-exome sequence data of selected members of these unique pedigrees and whole genome sequencing is ongoing for larger numbers of individuals from the most informative families. Dr. Bailey-Wilson is working with Drs. Forbes Porter of NICHD/NIH and Elaine Tierney of Kennedy Krieger Institute on a genetic study of autism. Evidence for linkage of autistic individuals with hypocholesterolemia has been found. Confirmation in additional data is underway and additional family data are being collected. Special funding from the Office of the Director was sought and awarded to perform whole-exome sequencing of autistic patients with extreme cholesterol values and a sibling with either autism or autism spectrum disorder (ASD) to search for rare variants of large effect in this subset of patients with familial autism/ASD. Whole exome sequence data for about one-half of the planned families is being analyzed and additional families will be sequenced over the next two years. We have also entered into collaboration with Drs. Sue Swedo and Audrey Thurm of NIMH/NIH to perform WES of their very well phenotyped parent-child trios and families where at least one child is affected with autism. Dr. Bailey-Wilson is collaborating with Dr. John Heiss on a study of Chiari Syndrome in Russia. This rare neurological syndrome is observed at increased frequency in several large families from a founder region there. Linkage analyses have recently been completed in these families and DNA sequencing to follow-up the most significant results is planned. Dr. Bailey-Wilson also serves in an advisory role on study design and interpretation of results for the Familial Intracranial Aneurysm (IA) consortium. This consortium is using both linkage and genome-wide association methods to detect genetic predisposition to this type of familial strokes. Results of a 6000 SNP genome-wide linkage study previously yielded evidence for linkage of IA on chromosome 4q and chromosome 12p. Significant evidence for a gene x smoking interaction was detected on chromosome 7p. These results suggest it is unlikely that there is a single common variant with a strong effect in the majority of the IA families. Rather, it is likely that multiple genetic and environmental risk factors contribute to the susceptibility for intracranial aneurysms. Linkage analysis using the broadest disease phenotype, including IA, abdominal AA, and thoracic AA, showed evidence for linkage on chromosomes 11 and 6, which supports the concept of shared genetic risk for these different types of aneurysm. We are now pursuing GWAS and DNA sequencing analyses in these data and a manuscript is under review. Dr. Bailey-Wilson also collaborates with Dr. Joan Marini of NICHD on studies of mutation age in a rare disorder, Lethal Recessive Type VIII Osteogenesis Imperfecta, in West Africans and African Americans. A paper reporting these results was published this year. Dr. Bailey-Wilson is also collaborating with Dr. Larry Brody and Dr. Alexander Wilson of NHGRI on analyses of GWAS data on metabolic traits in the Trinity Study. This work is ongoing, several papers are in preparation and one manuscript is under review.